Obesity and liver cancer: A key role for interleukin-6 and signal transducer and activator of transcription 3?


  • Potential conflict of interest: Nothing to report.

Park EJ, Lee JH, Yu G-Y, He G, Ali SR, Ryan G. Holzer, et al. Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression. Cell 2010;140:197-208. (Reprinted with permission.)


Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumorpromoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.


In the last decade, a number of large-scale epidemiological studies revealed that overweight and obesity are associated with a significant increase in cancer risk. The increase in risk was shown to be clearly dependent on the individual type of cancer. Strikingly, among all studied cancers, occurrence and progression of hepatocellular carcinoma (HCC) was the cancer most strongly affected by obesity, with an increase of relative risk of 4.52-fold for men with a body mass index between 35 and 40.1, 2 Indeed, because it correlates to the epidemiological spread of obesity in the developed world, HCC has risen to become the fifth most common cancer worldwide in the last decade.3

Although epidemiological studies are effective in identifying risk factors for diseases, they often fail to uncover the underlying mechanisms. Correlation studies proposed different mechanisms to explain how obesity increases cancer risk. It was, for example, mentioned that type 2 diabetes mellitus and insulin resistance, both frequent complications of malnutrition and obesity, lead to elevated concentrations of insulin and insulin-like growth factor 1 and could thereby increase tumor cell proliferation and growth. Furthermore, it was claimed that an increased production of sex steroids and cytokines by adipose tissue may give rise to tumor development. However, at present, none of these theories has been evaluated in animal models.4

Hepatosteatosis, which is characterized by an intrahepatic accumulation of lipids, is a frequent consequence of malnutrition and obesity. Nutritional insults induce reactive oxygen species, leading to the production of proinflammatory cytokines and recruitment of immune cells to the liver.5 The disease eventually progresses into nonalcoholic steatohepatitis (NASH), which was recently described as a main risk factor for HCC, thus providing a possible link between metabolic disorders, inflammation and development of cancer.6 Indeed, Wang et al. recently showed that consumption of a high-fat diet (HFD) resulted in a NASH-like intrahepatic accumulation of lipids and immune cells and increased formation of preneoplastic lesions in livers of rats treated with diethylnitrosamine (DEN).7 Luedde et al. reported that HFD consumption accelerated the appearance of liver tumors in NemoΔhep mice, which display a phenotype of liver damage, hepatosteatosis, and HCC even when kept on a normal diet.8 However, both studies failed to conclusively demonstrate that obesity per se rather than chronic liver damage causes tumor promotion, highlighting the need for further, more mechanistically focused studies.

To elucidate the mechanisms leading from obesity and steatosis to HCC, Park et al. in their recent article, applied the well-established DEN model for tumor induction in wild-type mice.9 They first demonstrated that mice kept on a HFD exhibited greatly enhanced HCC development compared to nonobese mice when treated with DEN. In line with these findings, Park et al. described that also leptin-deficient obese mice display greatly enhanced HCC development relative to wild-type mice after administration of DEN.

DEN-related tumor induction was previously linked to enhanced hepatocyte death and thereby compensatory hepatocyte proliferation.10 Conversely, Park et al. describe reduced apoptosis and enhanced cell proliferation in HCC of obese mice as compared to HCC of mice placed on a low-fat diet. In line with these findings, transplantation of hepatoma cells into lean mice that were placed on low-fat diet/HFD after inoculation of the cells revealed that the degree of host obesity determined tumor growth. This suggests that alterations in signal transduction pathways that modulate tumor cell proliferation independently of liver damage and compensatory proliferation may underlie the tumor-promoting effect of obesity. Indeed, Park et al. describe elevated c-Jun N-terminal kinase (JNK) activity and increased phosphorylation of the mammalian target of rapamycin (mTOR) target S6 kinase and its substrate ribosomal protein S6 in obese mice. Furthermore, HCCs in obese mice exhibited greatly elevated activity of both pro-oncogenic and inflammatory pathways such as extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3). Obesity also enhanced interleukin-6 (IL-6) messenger RNA and tumor necrosis factor (TNF) and IL-1b expression in both nontumor liver and HCC. As a corroboration of these data, growth of transplanted hepatoma cells can be slowed by administration of a JAK (Janus kinase) inhibitor that prevents STAT3 activation.

Enhanced activity of STAT3, a major transcriptional target for IL-6, was previously linked to development of HCC in humans. Furthermore, He et al. demonstrated that IL-6 is required for HCC development and that circulating IL-6 is elevated in cirrhosis and HCC.11 In their study,9 Park et al. used IL-6−/− mice to elucidate whether IL-6 is an important component of tumor promotion in the context of obesity. As previously described, deletion of IL-6 protected mice from DEN-induced HCC development when the mice were kept on a low-fat diet. Furthermore, no increase in tumor formation and growth was observed when these mice were in kept on a HFD. Interestingly tumor load in male IL-6-/- mice was similar to that of wild-type female mice, but unlike wild-type females, which develop more HCC when rendered obese, no significant increase in tumor load was described in obese IL-6-/- males.

Besides higher IL-6 expression, TNF has also been shown to be up-regulated in the context of obesity and HCC development. Strikingly, ablation of TNF receptor 1 (TNFR1) also abolished obesity-enhanced HCC development in DEN-treated mice; this was linked to the lack of increase in IL-6 expression in this scenario. Absence of IL-6 and TNFR1 reduced liver lipid accumulation (hepatosteatosis) and, importantly, also fat-induced liver inflammation (steatohepatitis) in HFD-fed IL-6−/− and TNFR1−/− mice. Furthermore, these deletions prevented the obesity-induced increase in JNK and ERK, as well as STAT3 phosphorylation in nontumor liver and HCC. Interestingly, the IL-6 or TNFR1 deficiency also prevented much of the obesity-induced increase in S6 phosphorylation and at least partially attenuated the decrease in AKT. Thus, Park et al. concluded that both IL-6 and TNF signaling via TNFR1 are important to trigger NASH, a condition that greatly increases the risk of HCC development (Fig. 1).

Figure 1.

Working model explaining HCC development following DEN treatment in obese mice. IL-6 release by inflammatory cells leads to STAT3 activation in hepatocytes. STAT3 stimulates progression and proliferation of predamaged hepatocytes and may be considered as a molecular trigger of tumor promotion.

Taken together, in their elegant work, Park et al. for the first time demonstrated that obesity is a bona fide tumor promoter for the development of HCC. Intrahepatic accumulations of lipids lead to chronic inflammation and thereby to chronic STAT3 activation via increase of TNF/IL-6 release. STAT3 was shown to stimulate the proliferation and progression of initiated hepatocytes into HCC and was identified as a molecular mediator of tumor promotion in the context of obesity. Although the mechanism for cancer development provided by Park et al. contributes greatly to our understanding of DEN-induced hepatocarcinogenesis, it is unlikely that elevated IL-6 and activated STAT3 cause cancer on their own in the setting of obesity. More likely, the combination of chronic activation of the IL-6/STAT3 axis and other factors such as mTOR signaling may trigger obesity-related HCC development. Indeed, it was previously reported that the mTOR signaling pathways are overexpressed in the context of HCC. Furthermore, Huyhn et al. reported that inhibition of the mTOR pathway by RAD001 or a rapamycin/bevacizumab combination resulted in tumor growth inhibition in mouse HCC models, thereby providing novel therapeutic approaches for HCC treatment.12